In This Issue:

Toward the $1,000 Genome:
Personalized Medicine

Genomics is the driving force for new discoveries in biomedical research. Recent discoveries in genomics have reshaped our understanding of how the human genome functions. These findings include the discovery that the majority of the DNA in the human genome is transcribed into RNA, and that these transcripts extensively overlap one another. The data also indicate that the human genome contains very little unused sequence and is a complex interwoven network in which protein-coding genes are just one of many types of DNA sequences that have a functional impact. These new discoveries will drive the continued development of accurate, cost-effective and high-throughput DNA sequencing technologies to decipher the functions of the complex genome for applications in clinical medicine and health care.

The health care, pharmaceutical development and medical research would greatly benefit from accurate and economical high-throughput DNA sequencing technologies capable of exploring the complete human genome sequence. It currently costs around $10 million to sequence 3 billion base pairs – the amount of DNA found in the human genome. In order to understand why some people develop certain diseases while others do not, scientists must compare the DNA sequences of a large population of people, including the healthy and those who are inflicted with the disease. However, due to the high costs to sequence the genome for one individual, it is currently not possible to have a platform that aims to tailor health-care and medicine based on a patient’s genetic makeup, a paradigm for personalized medicine.

In August 2007, the National Institutes of Health (NIH) has awarded more than $15 million in grants to support development of innovative technologies with the potential to dramatically reduce the cost of DNA sequencing so that an individual’s genome can be sequenced as a routine part of medical research and health care. Researchers from Columbia’s Fu Foundation School of Engineering and Applied Science received a $2.8 million grant from this initiative to develop novel molecular engineering approaches to decipher the genome on a chip. NIH’s near-term goal is to lower the cost of sequencing a mammalian-sized genome to $100,000, allowing researchers to sequence the genomes of hundreds or even thousands of people as part of studies to identify genes that contribute to common, complex diseases. Ultimately, NIH’s vision is to cut the cost of whole-genome sequencing to $1,000 or less, which will enable the sequencing of individual genomes as part of routine medical care.

Prof. Jingyue Ju

The Columbia research team, led by Jingyue Ju, Ph.D., Professor of Chemical Engineering, Director of the Center for Genome Technology and Biomolecular Engineering, and Head of DNA Sequencing and Chemical Biology at the Columbia Genome Center, aims to further develop the sequencing by synthesis platforms using a molecular engineering approach— the design and synthesis of novel fluorescent nucleotide reversible terminators. Since 2004, the NIH has supported Dr. Ju’s work in the research and development of novel DNA sequencing approaches with a total of $5.6 million of grant covering the following research projects: (1) An Integrated System for DNA Sequencing by Synthesis; (2) Modulating Nucleotide Size in DNA for Detection by Nanopore at the Single Molecule Level; and (3) 3’-O-Modified Nucleotide Reversible Terminators for Pyrosequencing.

The research progress in the development of these new genomic approaches has put Columbia University as a leading center in genomics and genome technology. In the upcoming 2007 International Conference on Genomics in Shenzhen-Hong Kong, Dr. Ju will serve as a Chairman of this important international genomics conference. Thus far, in addition to the genome technology funding of $5.6 million, the NIH has provided $14 million to support the research efforts in Columbia’s Center for Genome Technology and Biomolecular Engineering with its Centers of Excellence in Genomic Science program. These research efforts, led by Dr. Ju, Dr. Nicholas Turro, Professor of Chemistry, and Nobel Laureate Eric Kandel at Columbia University, bring together a team of chemical engineers, chemists, neurobiologists, and experts in informatics and genetic development—the best minds in the university with the greatest expertise to study the function of genes in the nervous system and the molecular basis of disease using the new genomic approaches and molecular imaging tools developed in the Columbia center.

“Our previous research, generously supported by NIH, has established the feasibility of using fluorescent nucleotide reversible terminators to sequence DNA immobilized on a chip. We have also shown that the nucleotide reversible terminator approach can overcome the difficulties in deciphering repetitive regions of DNA templates in pyrosequencing. The continued NIH support will allow us to further improve the sequencing chemistry and the associated sample preparation methods so that they can be quickly implemented to pursue cutting edge biomedical research projects, ” said Dr. Ju.

DNA sequencing on a chip

With more than six years of vigorous research, Dr. Ju’s laboratory, in collaboration with Dr. Nicholas Turro and his research team, have published numerous research articles, including seven papers published in the scientific journal Proceedings of the National Academy of Sciences (PNAS), firmly establishing the feasibility of using novel fluorescent nucleotides for DNA sequencing on a chip, which is a key step in advancing the field of DNA sequencing by synthesis through fluorescence imaging or by single molecule detection. The general strategy to rationally design cleavable fluorescent nucleotide reversible terminators for DNA sequencing by synthesis outlined in these publications from Columbia University is the basis for the newly developed next generation DNA sequencer. This new DNA sequencing system, based on the principles first developed by Dr. Ju and his Columbia colleagues, have already found wide applications in genome biology, ranging from whole genome sequencing to tag sequencing for the investigation of gene regulation to digital gene expression to discover rare and important genes that are responsible for specific biological functions and processes. With further development, the new genome technology platform invented at Columbia has the potential to realize the goals of personalized medicine based on an individual’s genetic profile. The ability to sequence an individual genome cost-effectively could enable health care professionals to tailor diagnosis, treatment and prevention to each person’s unique genetic profile, which will revolutionize medicine and healthcare.

The Center for Genome Technology and Biomolecular Engineering at the Columbia SEAS has established broad collaborations with scientists from Columbia and other research institutions in New York City with great accomplishments in new discoveries and inventing new technologies to study biomedical problems. This includes a collaboration with SEAS’s Department of Chemical Engineering Prof. Jeffrey Koberstein, who has developed new surfaces for biological molecule immobilization; with Prof. Timothy Bestor of Department of Genetics and Development, Columbia University Medical Center, leading to the characterization of the human genome methylation landscape; with Prof. Ian Lipkin at the Columbia Mailman School of Public Health, leading to the development of a novel digital high sensitive multiplex virus detection technology that has been used to discover new viruses, and implemented by the World Health Organization; and collaboration with Prof. Thomas Tuschl of Rockefeller University, leading to the discovery of piRNAs that play important roles in mammalian spermatogenesis.

Toward the $1,000 Genome: Personalized Medicine

Toward the $1,000 Genome:
Personalized Medicine